The dopamine D3 receptor has continued to be one of the most challenging targets for PET radiotracer development in the field of CNS receptor research. This difficulty has been largely based on the high degree of sequence homology between D2 and D3 receptors in the ligand binding region of each receptor. Although the past decade has witnessed a number of compounds having a high affinity and selectivity for D3 vs. D2 receptors, and many of these have been labeled with either carbon-11 or fluorine-18, none has proven to be successful in imaging the D3 receptor without the cross-over labeling of the D2 receptor. As described in the progress report, we have developed a D3-selective radiotracer, [18F] Fluortriopride (FTP) that has shown promising results in preliminary first-in-human PET studies. One of the conclusions reached in the progress report is that [18F]FTP binds to the orthosteric site in the D3 receptor, which results in a competition between dopamine (DA) and radiotracer for binding to the D3 receptor. Therefore, [18F] FTP measures D3 availability, which represents the number of D3 receptors that does not have DA bound to the orthosteric site. The first goal of the research described in this competing renewal is to conduct a detailed first- in-man study to fully characterize the ability of [18F] FTP to measure D3 receptor availability. A second goal is to identify a PET radiotracer that is insensitive to endogenous dopamine levels so that it is capable of imaging the density of D3 receptor in vivo. The project described in this grant proposal involves the continuation of a long-standing collaboration with the P.I. (RH Mach) and an expert in the field of dopamine receptor pharmacology (R.R. Luedtke). These investigators have a total of 38 joint publications in the field of dopamine receptor pharmacology. This project consists of five Specific Aims. The first Specific Aim consists of the first-in-human studies of [18F] FTP. The second Specific Aim describes a detailed structure-activity relationship study that will be conducted on two series of compounds with the goal of identifying the properties needed to develop a D3- selective probe whose in vivo binding is not influenced by synaptic dopamine levels. The compounds synthesized in Aim 2 will be screened in a series of in vitro binding studies described in Specific Aim 3. Specific Aim 4 involves the development of the radiosynthetic methods needed to conduct the rodent and nonhuman primate imaging described in Specific Aim 5. We anticipate generating one PET radiotracer that displays the affinity, specificity, and in vivo kinetics needed for translational imaging studies i human subjects by the completion of this 5-year research project.